Candida albicans is an opportunistic fungal pathogen that causes oropharyngeal infections in immunocompromised patients, including those with AIDS. It is usually one of the first clinical signs to appear as HIV-infected individuals progress o AIDS, and leads to serious morbidity if untreated. The azole class of antifungal drugs is currently used to prevent and treat oropharyngeal candidiasis. However, the emergence of drug resistant strains now makes it critical to develop new therapeutic strategies for oropharyngeal candidiasis. A key step in establishing C. albicans infections is the ability of this organism to grow invasively into epithelial tissues. To better define the mechanisms of C. albicans pathogenesis, studies are proposed to identify genes needed for invasive growth of C. albicans. This process has not been assessed systematically in previous studies of oropharyngeal candidiasis. Therefore, collections of C. albicans deletion mutants that have become available were screened to identify a broad set of genes needed for invasive growth into agar medium in vitro. Screening conditions were optimized to identify strongly defective mutants. The first goal will be to determine which of the mutants are defective in invading epithelial cells in vitro. Mutants with strong defects will then be examined for ability to undergo invasive hyphal growth into engineered mucosal cell layers. Those mutants observed to have significant defects in vitro will then be tested for ability to cause oropharyngeal candidiasis in mice, which serves as a good model for the human disease. These studies will reveal novel mechanisms involved in invasive growth, since about half of the mutants affect genes that have not been studied in any detail previously. The results are expected to identify new pathways that are critical for C. albicans to undergo invasive growth and cause oropharyngeal candidiasis in AIDS patients. These pathways will be targeted in future studies to develop novel therapeutic approaches.